Systemic sclerosis (SSc) is a complex and clinically heterogeneous orphan disease associated with reduced survival. To date, there is no approved therapy for SSc. While the fundamental pathogenic role of persistent fibroblast activation in fibrosis is well established, the underlying mechanisms remain poorly understood. Recent evidence suggests a biological connection between fibrosis and sirtuin (SIRT)-mediated cellular processes that govern aging. SIRTs are NAD-dependent nuclear and mitochondrial deacetylases, and their dysfunction is linked to age-associated pathologies. We made the novel observation that SIRT1 expression and activity is selectively down-regulated in skin biopsies from patients with SSc. Furthermore, we demonstrated that SIRTs exerted potent inhibitory effects on fibrotic responses in both normal and SSc fibroblasts in vitro, ameliorated skin fibrosis in vivo, and even partial reduction in levels resulted in exaggerated fibrosis. Based on our findings, we hypothesize that impaired SIRT expression and function is contributes to fibrosis in SSc, and restoring SIRT activity represses fibroblast activation and represents a potential therapeutic strategy. To test this novel hypothesis, this proposal will evaluate the pathogenic roles of SIRTs in distinct and complementary mouse models of scleroderma; determine the effects and mechanism of action of pharmacologically modulating SIRT activity on the disease process; explore the cellular mechanisms and key molecular mediators for SIRT anti-fibrotic activity, focusing on TGF-beta signaling; and examine if altered SIRT expression or function in SSc is associated with disease severity or progression. We will address these interrelated questions by a comprehensive experimental approach utilizing human and mouse cells, transgenic mouse strains, novel translationally-relevant SIRT modulators, and annotated patient samples. We expect that these studies will identify novel roles and mechanism of action of SIRTs and their modulators in fibrotic cellular responses and experimental fibrosis. Additionally, our results might uncover novel disease biomarkers in SSc. We anticipate that novel mechanistic insights from these studies will significantly advance the understanding of SSc. Furthermore, our studies will help set a framework for innovative SSc therapies targeting SIRT signaling.